Neurodegenerative diseases represent a significant human, societal and economic burden. This term includes brain diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or Amyotrophic Lateral Sclerosis (ALS). PD, the second most common neurodegenerative disease in older adults, affects more than 6.3 million people worldwide. Neurodegenerative diseases are characterized by progressive degeneration of neurons in specific functional systems of the central nervous system, such as death of dopaminergic neurons in PD. The progressive loss of structure and function of neurons in neurodegenerative diseases, such as PD, involves mitochondrial dysfunction and axonal degeneration (1, 2).
Despite considerable efforts, we still lack efficient therapies to block neuronal demise in the early stages of neurodegeneration. Accordingly, there is an urgent need to develop new approaches and drugs that will be suitable for effective and efficient treatment of neurodegenerative disorders and which could significantly retard disease progression. In this way, it has been suggested that characterization of new therapeutic compounds in neurodegenerative disorders inducing protection of neurons from degeneration associated with the preservation of mitochondrial functions and enhanced mitochondrial filamentation may be highly desirable.
Viruses, as obligatory parasites, have evolved highly specific means to hijack cellular pathways. In order to optimize the survival in their host, many viruses express proteins, or non-coding RNA, that block or delay the death of infected cells by acting at the mitochondrial level (3-5). In particular, some neurotropic viruses have very efficient strategies to protect neurons, given that their target cells have a very poor capacity of renewal. A case in point is Bornavirus (or BDV), a highly neurotropic RNA virus that persists in the brain of many animal species without causing direct damage to neurons (6). BDV non-cytolytic replication is due to the expression of an 87 amino acids viral protein called X that targets mitochondria in the infected cells (7).
Here, the inventors investigated the possibility that the X protein could protect neurons against neurodegenerative insults, even when used outside of the viral context. In particular, the inventors assessed protection against mitochondrial respiratory complex I toxins, which induce oxidative stress and neurodegeneration in tissue culture and in animal models (8-11).
There is no disclosure in the art of protein X-derived peptide effects in neurodegenerative disorders, protection of neurons from degeneration associated with the preservation of mitochondrial functions and enhanced mitochondrial filamentation and the use of the protein X-derived peptide in the treatment of neurodegenerative disorders, and the induction of hyperfilamentation of the mitochondrial network.